Global mean surface temperature and climate sensitivity of the early Eocene Climatic Optimum (EECO), Paleocene–Eocene Thermal Maximum (PETM), and latest Paleocene

Accurate estimates of past global mean surface temperature (GMST) help to contextualise future climate change and are required to estimate the sensitivity of the climate system to CO2 forcing through Earth's history. Previous GMST estimates for the latest Paleocene and early Eocene (∼57 to 48 million years ago) span a wide range (∼9 to 23 ∘C higher than pre-industrial) and prevent an accurate assessment of climate sensitivity during this extreme greenhouse climate interval. Using the most recent data compilations, we employ a multi-method experimental framework to calculate GMST during the three DeepMIP target intervals: (1) the latest Paleocene (∼57 Ma), (2) the Paleocene–Eocene Thermal Maximum (PETM; 56 Ma), and (3) the early Eocene Climatic Optimum (EECO; 53.3 to 49.1 Ma). Using six different methodologies, we find that the average GMST estimate (66 % confidence) during the latest Paleocene, PETM, and EECO was 26.3 ∘C (22.3 to 28.3 ∘C), 31.6 ∘C (27.2 to 34.5 ∘C), and 27.0 ∘C (23.2 to 29.7 ∘C), respectively. GMST estimates from the EECO are ∼10 to 16 ∘C warmer than pre-industrial, higher than the estimate given by the Intergovernmental Panel on Climate Change (IPCC) 5th Assessment Report (9 to 14 ∘C higher than pre-industrial). Leveraging the large “signal” associated with these extreme warm climates, we combine estimates of GMST and CO2 from the latest Paleocene, PETM, and EECO to calculate gross estimates of the average climate sensitivity between the early Paleogene and today. We demonstrate that “bulk” equilibrium climate sensitivity (ECS; 66 % confidence) during the latest Paleocene, PETM, and EECO is 4.5 ∘C (2.4 to 6.8 ∘C), 3.6 ∘C (2.3 to 4.7 ∘C), and 3.1 ∘C (1.8 to 4.4 ∘C) per doubling of CO2. These values are generally similar to those assessed by the IPCC (1.5 to 4.5 ∘C per doubling CO2) but appear incompatible with low ECS values (<1.5 per doubling CO2)

Incidence of and socio-biologic risk factors for spontaneous preterm birth in HIV positive Nigerian women

BACKGROUND: Recent studies have identified HIV as a leading contributor to preterm delivery and its associated morbidity and mortality. However little or no information exists in our sub-region on this subject. Identifying the factors associated with preterm delivery in HIV positive women in our country and sub-region will not only prevent mother to child transmission of HIV virus but will also reduce the morbidity and mortality associated with prematurity and low birth weight. This study was designed to determine the incidence and risk factors for preterm delivery in HIV positive Nigerians. METHOD: The required data for this retrospective study was extracted from the data base of a cohort study of the outcome of prevention of mother to child transmission at the Nigerian Institute of Medical Research, Lagos. Only data of women that met the eligibility of spontaneous delivery after 20 weeks of gestation were included. Ethical approval was obtained from the Institution’s Ethical Review Board. RESULTS: 181 women out of the 1626 eligible for inclusion into the study had spontaneous preterm delivery (11.1%). The mean birth weight was 3.1 ± 0.4 kg, with 10.3% having LBW. Spontaneous preterm delivery was found to be significantly associated with unmarried status (cOR: 1.7;1.52-2.57), baseline CD4 count <200 cells/mm(3)(cOR: 1.8; 1.16-2.99), presence of opportunistic infection at delivery (cOR: 2.2;1.23-3.57), multiple pregnancy (cOR 10.4; 4.24 – 26.17), use of PI based triple ARV therapy (eOR 10.2; 5.52 – 18.8) in the first trimester (cOR 2.5; 1.77 – 3.52) on univariate analysis. However after multivariate analysis controlling for potential confounding variables including low birth weight, only multiple pregnancy (aOR: 8.6; CI: 6.73 – 12.9), presence of opportunistic infection at delivery (aOR: 1.9; CI: 1.1 – 5.7), and 1st trimester exposure to PI based triple therapy (aOR: 5.4; CI: 3.4 – 7.8) retained their significant association with preterm delivery. CONCLUSION: The spontaneous preterm delivery rate among our cohort was 11.1%. HIV positive women with multiple pregnancies, symptomatic HIV infection at delivery and first trimester fetal exposure to PI based triple therapy were found to be at risk of spontaneous preterm delivery. Early booking and non-use of PI based triple therapy in the first trimester will significantly reduce the risk of preterm delivery

The 4 Youth By Youth mHealth Photo Verification App for HIV Self-testing in Nigeria: Qualitative Analysis of User Experiences.

BACKGROUND: Despite the global expansion of HIV self-testing (HIVST), many research studies still rely on self-reported outcomes. New HIVST verification methods are needed, especially in resource-limited settings. OBJECTIVE: This study aims to evaluate the user experience of a mobile health (mHealth) app to enhance HIVST result reporting and verification. METHODS: Semistructured, in-depth interviews were used to evaluate the user experience of the 4 Youth By Youth mHealth photo verification app for HIVST. We used a think-aloud approach, and participants performed usability tasks and completed a qualitative exit interview. The app included HIV educational resources, step-by-step video instructions for performing HIVST, a 20-minute timer, a guide on interpreting results with linkages to care, an offline version, and a photo verification system. Demographic characteristics were reported by using descriptive statistics. Qualitative data were analyzed by using thematic analysis. RESULTS: A total of 19 users-12 women and 7 men-with a mean age of 22 years, participated in the study. The users completed the usability tasks and successfully uploaded a photo of their test results by using the app without assistance. Four main themes were identified in the data. First, in terms of user-friendly design, the participants noted the user-friendly features of the offline version and the app's low data use. However, some wanted the app to work in the background when using their mobile phone, and the font used should be more youth friendly. Second, in terms of ease of use, participants remarked that the app's self-explanatory nature and instructions that guided them on how to use the app enhanced its use. Third, in terms of a user's privacy, many participants reinforced the importance of privacy settings and tools that protect confidentiality among users. Finally, in terms of linkage to care, participants noted that the app's linkage to care features were useful, particularly in relation to referrals to trained counselors upon the completion of the test. All the participants noted that the app provided a convenient and private means of verifying the HIV test results. CONCLUSIONS: Our findings demonstrated the importance of engaging end users in the development phase of health technology innovations that serve youth. Clinical trials are needed to determine the efficacy of using an mHealth app to verify HIVST results among young people

Retention of uninfected red blood cells causing congestive splenomegaly is the major mechanism of anemia in malaria

Splenomegaly frequently occurs in patients with Plasmodium falciparum (Pf) or P. vivax (Pv) malarial anemia, but mechanisms underlying this co-occurrence are unclear. In malaria-endemic Papua, Indonesia, we prospectively analyzed red blood cell (RBC) concentrations in the spleen and spleen-mimetic retention in 37 subjects splenectomized for trauma or hyperreactive splenomegaly, most of whom were infected with Plasmodium. Splenomegaly (median 357 g [range: 80-1918 g]) was correlated positively with the proportion of red-pulp on histological sections (median 88.1% [range: 74%-99.4%]; r = .59, p = .0003) and correlated negatively with the proportion of white-pulp (median 8.3% [range: 0.4%-22.9%]; r = -.50, p = .002). The number of RBC per microscopic field (>95% uninfected) was correlated positively with spleen weight in both Pf-infected (r = .73; p = .017) and Pv-infected spleens (r = .94; p = .006). The median estimated proportion of total-body RBCs retained in Pf-infected spleens was 8.2% (range: 1.0%-33.6%), significantly higher than in Pv-infected (2.6% [range: 0.6%-23.8%]; p = .015) and PCR-negative subjects (2.5% [range: 1.0%-3.3%]; p = .006). Retained RBCs accounted for over half of circulating RBC loss seen in Pf infections. The proportion of total-body RBC retained in Pf- and Pv-infected spleens correlated negatively with hemoglobin concentrations (r = -.56, p = .0003), hematocrit (r = -.58, p = .0002), and circulating RBC counts (r = -.56, p = .0003). Splenic CD71-positive reticulocyte concentrations correlated with spleen weight in Pf (r = 1.0; p = .003). Retention rates of peripheral and splenic RBCs were correlated negatively with circulating RBC counts (r = -.69, p = .07 and r = -.83, p = .008, respectively). In conclusion, retention of mostly uninfected RBC in the spleen, leading to marked congestion of the red-pulp, was associated with splenomegaly and is the major mechanism of anemia in subjects infected with Plasmodium, particularly Pf

A designathon to co-create community-driven HIV self-testing services for Nigerian youth: findings from a participatory event.

BACKGROUND: Youth are at high risk for HIV, but are often left out of designing interventions, including those focused on adolescents. We organized a designathon for Nigerian youth to develop HIV self-testing (HIVST) strategies for potential implementation in their local communities. A designathon is a problem-focused event where participants work together over a short period to create and present solutions to a judging panel. METHODS: We organized a 72-h designathon for youth (14-24 years old) in Nigeria to design strategies to increase youth HIVST uptake. Proposals included details about HIVST kit service delivery, method of distribution, promotional strategy, and youth audience. Teams pitched their proposals to a diverse seven-member judging panel who scored proposals based on desirability, feasibility, potential impact and teamwork. We examined participants' socio-demographic characteristics and summarized themes from their HIVST proposals. RESULTS: Forty-two youth on 13 teams participated in the designathon. The median team size was 3 participants (IQR: 2-4). The median age was 22.5 years (IQR: 21-24), 66.7% were male, 47.4% completed tertiary education, and 50% lived in Lagos State. Themes from proposals included HIVST integration with other health services, digital marketing and distribution approaches, and engaging students. Judges identified seven teams with exceptional HIVST proposals and five teams were supported for further training. CONCLUSIONS: The designathon provided a structured method for incorporating youth ideas into HIV service delivery. This approach could differentiate HIV services to be more youth-friendly in Nigeria and other settings

A Randomized Trial of Prophylactic Antibiotics for Miscarriage Surgery.

BACKGROUND: Surgical intervention is needed in some cases of spontaneous abortion to remove retained products of conception. Antibiotic prophylaxis may reduce the risk of pelvic infection, which is an important complication of this surgery, particularly in low-resource countries. METHODS: We conducted a double-blind, placebo-controlled, randomized trial investigating whether antibiotic prophylaxis before surgery to complete a spontaneous abortion would reduce pelvic infection among women and adolescents in low-resource countries. We randomly assigned patients to a single preoperative dose of 400 mg of oral doxycycline and 400 mg of oral metronidazole or identical placebos. The primary outcome was pelvic infection within 14 days after surgery. Pelvic infection was defined by the presence of two or more of four clinical features (purulent vaginal discharge, pyrexia, uterine tenderness, and leukocytosis) or by the presence of one of these features and the clinically identified need to administer antibiotics. The definition of pelvic infection was changed before the unblinding of the data; the original strict definition was two or more of the clinical features, without reference to the administration of antibiotics. RESULTS: We enrolled 3412 patients in Malawi, Pakistan, Tanzania, and Uganda. A total of 1705 patients were assigned to receive antibiotics and 1707 to receive placebo. The risk of pelvic infection was 4.1% (68 of 1676 pregnancies) in the antibiotics group and 5.3% (90 of 1684 pregnancies) in the placebo group (risk ratio, 0.77; 95% confidence interval [CI], 0.56 to 1.04; P = 0.09). Pelvic infection according to original strict criteria was diagnosed in 1.5% (26 of 1700 pregnancies) and 2.6% (44 of 1704 pregnancies), respectively (risk ratio, 0.60; 95% CI, 0.37 to 0.96). There were no significant between-group differences in adverse events. CONCLUSIONS: Antibiotic prophylaxis before miscarriage surgery did not result in a significantly lower risk of pelvic infection, as defined by pragmatic broad criteria, than placebo. (Funded by the Medical Research Council and others; AIMS Current Controlled Trials number, ISRCTN97143849.)

Global and Zonal-Mean Hydrological Response to Early Eocene Warmth

Earth's hydrological cycle is expected to intensify in response to global warming, with a “wet-gets-wetter, dry-gets-drier” response anticipated over the ocean. Subtropical regions (∼15°–30°N/S) are predicted to become drier, yet proxy evidence from past warm climates suggests these regions may be characterized by wetter conditions. Here we use an integrated data-modeling approach to reconstruct global and zonal-mean rainfall patterns during the early Eocene (∼56–48 million years ago). The Deep-Time Model Intercomparison Project (DeepMIP) model ensemble indicates that the mid- (30°–60°N/S) and high-latitudes (>60°N/S) are characterized by a thermodynamically dominated hydrological response to warming and overall wetter conditions. The tropical band (0°–15°N/S) is also characterized by wetter conditions, with several DeepMIP models simulating narrowing of the Inter-Tropical Convergence Zone. However, the latter is not evident from the proxy data. The subtropics are characterized by negative precipitation-evaporation anomalies (i.e., drier conditions) in the DeepMIP models, but there is surprisingly large inter-model variability in mean annual precipitation (MAP). Intriguingly, we find that models with weaker meridional temperature gradients (e.g., CESM, GFDL) are characterized by a reduction in subtropical moisture divergence, leading to an increase in MAP. These model simulations agree more closely with our new proxy-derived precipitation reconstructions and other key climate metrics and imply that the early Eocene was characterized by reduced subtropical moisture divergence. If the meridional temperature gradient was even weaker than suggested by those DeepMIP models, circulation-induced changes may have outcompeted thermodynamic changes, leading to wetter subtropics. This highlights the importance of accurately reconstructing zonal temperature gradients when reconstructing past rainfall patterns

A randomized stepped wedge trial of an intensive combination approach to roll back the HIV epidemic in Nigerian adolescents: iCARE Nigeria treatment support protocol.

BackgroundNigeria is one of six countries with half the global burden of youth living with HIV. Interventions to date have been inadequate as AIDS-related deaths in Nigeria's youth have remained unchanged in recent years. The iCARE Nigeria HIV treatment support intervention, a combination of peer navigation and SMS text message medication reminders to promote viral suppression, demonstrated initial efficacy and feasibility in a pilot trial among youth living with HIV in Nigeria. This paper describes the study protocol for the large-scale trial of the intervention.MethodsThe iCARE Nigeria-Treatment study is a randomized stepped wedge trial of a combination (peer navigation and text message reminder) intervention, delivered to youth over a period of 48 weeks to promote viral suppression. Youth receiving HIV treatment at six clinical sites in the North Central and South Western regions of Nigeria were recruited for participation. Eligibility criteria included registration as a patient at participating clinics, aged 15-24 years, on antiretroviral therapy for at least three months, ability to understand and read English, Hausa, Pidgin English, or Yoruba, and intent to remain a patient at the study site during the study period. The six clinic sites were divided into three clusters and randomized to a sequence of control and intervention periods for comparison. The primary outcome is plasma HIV-1 viral load suppression, defined as viral load ≤ 200 copies/mL, in the intervention period versus the control period at 48 weeks of intervention.DiscussionEvidence-based interventions to promote viral load suppression among youth in Nigeria are needed. This study will determine efficacy of a combination intervention (peer navigation and text message reminder) and collect data on potential implementation barriers and facilitators to inform scale-up if efficacy is confirmed.Trial registrationClinicalTrials.gov number, NCT04950153, retrospectively registered July 6, 2021, https://clinicaltrials.gov/

Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial

BACKGROUND: Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19. METHODS: The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 μg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 μg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (anti-spike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing. FINDINGS: Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70·1 years (IQR 51·6-77·5) and 86 (52%) of 166 participants were female and 80 (48%) were male. The median interval between the third and fourth doses was 208·5 days (IQR 203·3-214·8). Pain was the most common local solicited adverse event and fatigue was the most common systemic solicited adverse event after BNT162b2 or mRNA-1273 booster doses. None of three serious adverse events reported after a fourth dose with BNT162b2 were related to the study vaccine. In the BNT162b2 group, geometric mean anti-spike protein IgG concentration at day 28 after the third dose was 23 325 ELISA laboratory units (ELU)/mL (95% CI 20 030-27 162), which increased to 37 460 ELU/mL (31 996-43 857) at day 14 after the fourth dose, representing a significant fold change (geometric mean 1·59, 95% CI 1·41-1·78). There was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25 317 ELU/mL, 95% CI 20 996-30 528) to 14 days after a fourth dose of mRNA-1273 (54 936 ELU/mL, 46 826-64 452), with a geometric mean fold change of 2·19 (1·90-2·52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12·19 (95% CI 10·37-14·32) and 15·90 (12·92-19·58) in the BNT162b2 and mRNA-1273 groups, respectively. T-cell responses were also boosted after the fourth dose (eg, the fold changes for the wild-type variant from before to after the fourth dose were 7·32 [95% CI 3·24-16·54] in the BNT162b2 group and 6·22 [3·90-9·92] in the mRNA-1273 group). INTERPRETATION: Fourth-dose COVID-19 mRNA booster vaccines are well tolerated and boost cellular and humoral immunity. Peak responses after the fourth dose were similar to, and possibly better than, peak responses after the third dose. FUNDING: UK Vaccine Task Force and National Institute for Health Research